PROJECT SUMMARY Mitral valve prolapse (MVP) is a common valvulopathy with a strong hereditary component affecting over 7 million individuals in the United States and over 170 million worldwide. A subset of MVP patients (0.8-2.5%) is at increased risk for cardiac arrest (SCA) or sudden cardiac death (SCD). Complex ventricular ectopy and repolarization abnormalities in the inferior ECG leads were reported in a malignant phenotype of bileaflet MVP associated with out-of-hospital SCA in the absence of significant mitral regurgitation. Focal myocardial fibrosis was demonstrated in the left ventricular papillary muscles or inferolateral base in autopsy studies and on cardiac magnetic resonance (CMR) in patients with MVP and complex ventricular arrhythmia, SCD or both. Moreover, we have shown that diffuse interstitial fibrosis by CMR is often present even without focal fibrosis in arrhythmic MVP, both with and without significant MR. Overall, the mechanism of ventricular arrhythmia in MVP remains poorly understood. Current knowledge about the association of MVP with SCD/SCA relies on retrospective evaluations or small autopsy studies. Therefore, guidelines for risk stratification of arrhythmic MVP cases are lacking and indications for implantable cardioverter defibrillator (ICD) placement in this subset of patients are unclear. In contrast to ?general? MVP, the genetic mechanisms and phenotype-genotype correlations underlying arrhythmic complications of MVP have yet to be investigated. Our central hypothesis is that among MVP genetic variants, some are associated with higher risk of SCD/SCA and can be identified through detailed assessment of human genotype-phenotype correlations in families. In the general population, future development of a prospective arrhythmic risk prediction model in an R01 application will require a large MVP cohort and follow-up of arrhythmic complications. Specifically, we aim to 1) perform whole-exome sequencing (WES) and use ECG/imaging in a preliminary subset of 3 MVP SCD/SCA pedigrees in order to identify early and advanced ECG/imaging features of arrhythmic risk and 2) test the feasibility of using the Health eHeart Study, a cardiovascular cohort with internet-based remote consent and ability to integrate longitudinal medical records to develop a prospective MVP cohort. The preliminary data obtained in this R03 application will improve SCD risk stratification, help establish the future need for an ICD in MVP and allow pre-symptomatic family screening.